WHICH CAME FIRST: THE CHICKEN OR THE CANCER VIRUS?

A virus, discovered 90 years ago in a chicken tumor, was the directional arrow that pointed to looking for cancer's cause in our own genes.

by Eva Emerson

Modern cancer research can be traced to modest beginnings-a chicken coop filled with tumor-ridden birds. In 1909, an upstate farmer brought one of his fowl to Francis Peyton Rous, a scientist at the Rockefeller Institute for Medical Research in New York City. Rous made an amazing discovery: the chicken's tumors were caused by an infection with a virus. What's more, he could infect a healthy chicken with "cancer" simply by injecting it with a solution taken from a sick hen's tumor. Cancer, Rous reasoned, was not only caused by a virus, it was potentially contagious.

Can you catch cancer? For much of this century, scientists thought so and searched in vain for viruses that caused cancer in humans. Although the theory that viruses are responsible for the majority of cancers has since fallen from favor, cancers of the liver, cervix and lymphatic system have all been traced to viruses. Scientists now believe that as many as 15 percent of cancer deaths worldwide may stem from viral infections.

But most importantly, the extensive search for cancer-causing viruses led to waves of discovery that opened up the current understanding of the roots of cancer: our own genes.

F i n d i n g  A  H u m a n  C a n c e r  V i r u s

"We started our search for the cause of cancer looking for human tumor viruses, similar to what we had seen in animals," recalls Brian Henderson, M.D., the Kenneth T. Norris Jr. Chair in Epidemiology and professor of preventive medicine.

The idea of an infectious virus causing cancer was appealing to scientists, admits virologist Michael Lai, M.D., Ph.D., professor of molecular microbiology and immunology and a Howard Hughes Medical Institute Investigator. "It would have made cancer a straightforward problem, one that scientists could battle with a vaccine, as they had so successfully with other viruses, like smallpox."

However, despite the isolation of many viruses that cause cancers in animals, the intense efforts to isolate human cancer viruses failed. It wasn't until the early 1980s when scientists at the National Cancer Institute and in Japan almost simultaneously isolated two related viruses that did cause cancer in humans. They were human T-cell leukemia virus type-1 and type-2 or HTLV, which brings on a rare cancer of the immune cells called adult T-cell leukemia. It is spread much like the AIDS virus, HIV: from mother-to-child during birth and breastfeeding; through sexual contact; and through exposure to contaminated blood.

"This virus fascinates cancer doctors because it was the first virus to be clearly connected to a human malignancy," says Alexandra Levine, M.D., professor and chief of hematology and medical director of the USC/Norris. To Levine, finding ways to treat patients who suffer from the rare lymphoma holds even more fascination. "Developing better clinical treatments for HTLV and HIV-associated cancers has been an area of tremendous research at the Norris," she says, noting that her group is usually involved in more than two dozen studies in these areas at any given time.

Levine and her colleagues, led by Parkash Gill, M.D., professor of medicine and pathology, have made headway developing one of the only effective treatments for the adult T-cell lymphoma that is caused by the HTLV virus. A combination of the antiviral drug AZT and interferon (an immune booster) worked in about half of patients that they treated.

Despite the interest it holds for cancer researchers, only about 5 percent of those infected with HTLV actually go on to develop cancer. "The risk of contracting the virus in the U.S. is relatively low, and, even if you do get infected with the virus, the chance of developing this lymphoma is even lower," Levine says.

A I D S  a n d  C a n c e r

HIV does not cause cancer, Levine is quick to remind people. But the virus does destroy the immune system, leaving a person without an important defense mechanism against the growth of cancer. "We all know the immune system battles infections. But what we've learned from studying HIV-associated cancers is just how critical the immune system is in protecting you against malignancy," she says.

The three most common types of cancer in patients with AIDS- Kaposi's sarcoma, non-Hodgkin's lymphoma and cervical cancer-have all been linked to viral infections. Two of the suspect viruses, the human papillomavirus and Epstein-Barr virus, have also been linked to cancers in people with a functioning immune system. But, it appears that AIDS patients may get these cancers at a higher incidence than the general population.

One of the culprits may be an extremely common virus that usually causes the short-lived mononucleosis, but also has been implicated in a wide variety of cancers-the Epstein-Barr virus. Besides its potential role in AIDS-associated lymphoma, the Epstein-Barr virus is also a suspect in Burkitt's lymphoma, cancer of the upper pharynx, and Hodgkin's disease.

Kaposi's sarcoma, tumors that often appear as purple-tinged patches on the skin, occurred rarely until the emergence of AIDS. Strong evidence links Kaposi's sarcoma (KS) to a virus. "We think that KS might be caused by a newly discovered strain of the human herpes virus," says Levine. Levine and Gill have helped test new treatments for KS. One drug, isolated by Gill from female hormones, appears to shrink tumors by cutting off their blood supply, and holds promise for treating other cancers.

S e x u a l l y  T r a n s m i t t e d  V i r u s e s  a n d  C a n c e r s

Studies have long shown a link between certain strains of the human papillomavirus and cervical cancer. The sexually transmitted human papillomaviruses (HPV) include those that cause genital warts and viruses that elicit no symptoms at all. Cervical cancer appears more common in women with AIDS. AIDS patients also have a higher rate of precancerous growth on the cervix, called dysplasia.

Like other cancer-associated viruses, the human papillomavirus can insert its genetic material into the DNA of host cells. This allows the virus to persist in the body for years, out of the immune system's reach. In this quiescent state, the virus carriers may not even know that they have been infected.

Just two strains of HPV appear to be responsible for the majority of the cases of genital and anal cancers around the world. However, the virus alone may not be enough to cause cancer. Of the millions of American women believed to carry the virus, only about 16,000 are diagnosed with cervical cancer each year.

"Eventually, we'd like to see a vaccine to prevent HPV infection, and thus cancer. It would be an enormous boon to women throughout the world," says C. Paul Morrow, M.D., director of gynecologic oncology and the Langmade Professor of Obstetrics and Gynecology.

A vaccine to treat women already infected with HPV is the goal of research headed by Jeffrey Weber, M.D., Ph.D., director of immunotherapy at USC/Norris, and Laila Muderspach, M.D., assistant professor of obstetrics and gynecology. They hope to prevent cervical cancer by helping the immune system to rid the body of the virus. Preliminary tests have shown that the vaccine can help clear the virus from the patient's blood, Weber says.

H e p a t i t i s  a n d  C a n c e r

"The most exciting link between viruses and cancer came out of a 1981 study of people with hepatitis B," says Henderson. "Chronic carriers of the virus had a phenomenal risk of developing liver cancer."

Epidemiologists estimate that all types of viral hepatitis are collectively responsible for approximately 80 percent of liver cancers worldwide. The hepatitis viruses that cause the worst damage are blood-borne and sexually transmitted.

Hepatitis B is riskiest for those infected as children- 90 percent become chronic carriers, notes Lai. "Chronic carrier" means a person in whom the virus remains active and can be transmitted. In contrast, only about 10 to 20 percent of those infected as adults become chronic carriers. With the introduction of a vaccine for hepatitis B in the 1980s, scientists finally got what they had long been looking for: "It is the first effective cancer vaccine in history," Lai says. Studies in Taiwan, where hepatitis is endemic and infants are now vaccinated, hint at reduced rates of liver cancer in children. Infants in the U.S. are now routinely immunized against hepatitis B. "In 20 to 30 years, we will probably see the rate of liver cancer in adults go down as well," Lai predicts.

Lai has shifted the focus of some of his research efforts to concentrate on the hepatitis C virus. Hepatitis C is different from hepatitis B, but shares the same target organ-the liver. The C virus was only discovered in 1989 and may be an even more deadly foe than the B virus.

Unlike hepatitis B, hepatitis C leads to chronic disease in the majority of cases. More than 4 million Americans are chronic carriers. About 20 percent of chronic carriers develop liver cirrhosis or liver cancer, making it the leading reason for liver transplantation.

Mimi Yu, Ph.D., professor of preventive medicine, was one of the first to establish a link between hepatitis C and liver cancer. Her ongoing study of liver cancer in black and white Americans in Los Angeles County has helped define a role for both hepatitis B and C in liver cancer in non-Asians.

"Outside of Asia and Africa, liver cancer is relatively rare," Yu says. That makes her database of liver cancer patients even more valuable. "As new hepatitis viruses are discovered, I can go back and test samples for the presence of the virus. That is how I showed the importance of the C virus. Now, I'm looking at a new hepatitis, the G virus. My studies show the G virus may also influence the development of liver cancer," she says.

"We know that some viruses are definitely associated with certain cancers. But by no means do all of these viruses act alone," Lai says.

C o m p l e x   C a u s e s

USC/Norris researchers have helped to show how a virus may interact with other factors to increase risk of cancer. In a study done in China, epidemiologists Ronald K. Ross, M.D., the Aresty Urologic Research Chair and professor of preventive medicine, Yu and Henderson showed that chronic infection with the hepatitis B virus and aflatoxin, a toxin produced by mold that grows on peanuts, corn and beans, increased cancer risk 12-fold over the risk associated with the virus alone.

Other researchers are hoping to discern the combined effects of two viruses on causing cancer.

Yu has shown that those who have both hepatitis B and C viruses face a much higher risk of liver cancer than those who have only one virus.

Levine's team looked at a large number of HIV-negative lymphoma patients and found that about 20 percent of B-cell lymphoma patients also carry hepatitis C. Studies at other universities have supported these findings. "We are beginning to understand lymphoma is not just caused by one thing, nor by one virus," Levine says.

Even with strong associations between viruses and cancer, "it is still not quite clear how all of these viruses act in cells to initiate cancer," says Lai.

A t  C a n c e r ' s  R o o t s ,  H u m a n  G e n e s

What is known about how viruses may bring on cancer can be traced back to the work of Rous and those chicken tumors. "Isolating the gene of the Rous sarcoma virus that initiated the tumor was the first evidence that pointed in the direction of where we should look for the true cause of cancer-the cell's own genes," Henderson says.

Lai adds, "Cancer genes [or oncogenes] are normal genes that play important roles in the body at various times in life, such as during early development. When they are turned on at the wrong time, they can convert a cell into a cancerous one."

Viruses, Lai says, turn on any of a host's oncogenes in one of two ways. During an infection, a virus may incorporate an oncogene into its own genetic blueprint. The virus may then be transformed into a tumor virus that can spread cancer. Another way is when a virus inserts viral genes into the host's genes. When this kind of gene splicing occurs near an oncogene, a virus may accidentally switch the oncogene on.

"Cancer is much more complex than originally thought," says Lai. "Many different pathways-viruses, chemicals, our own genes-lead to cancer. But they seem to use this common doorway, the oncogenes."

Lai points out that the study of cancer viruses opened new fields of inquiry into the roots of cancer-the oncogenes that initiate the growth of a tumor-and eventually revealed viruses as important causes of some cancers.

The inquiry underlines the critical nature of basic science research, says Lai. "It may not pay immediate dividends, but you may realize much later that you have made an important breakthrough."

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